The epidemiology of upper respiratory tract disorders in a population of insured Swedish dogs (2011–2014), and its association to brachycephaly

Upper respiratory tract (URT) disorders are common in dogs but neither general nor breed-related epidemiological data are widely reported. This study´s aims were to describe the epidemiology of URT disorders in a Swedish population of dogs and to investigate whether brachycephalic breeds were overrepresented among high-risk breeds. A cohort of dogs insured by Agria Djurförsäkring in Sweden (2011–2014) was used to calculate overall and breed-specific incidence rate (IR), age at first URT diagnosis and relative risk (RR) for URT disorders. For breeds with high RR for URT disorders, co-morbidities throughout the dog’s insurance period and age at death were investigated. The cohort included approximately 450,000 dogs. URT disorders had an overall IR of 50.56 (95% CI; 49.14–52.01) per 10,000 dog years at risk. Among 327 breeds, the English bulldog, Japanese chin, Pomeranian, Norwich terrier and pug had highest RR of URT disorders. Eight of 13 breeds with high RR for URT disorders were brachycephalic. The median age at first URT diagnosis was 6.00 years (interquartile range 2.59–9.78). French bulldogs with URT diagnoses had a significantly shorter life span (median = 3.61 years) than other breeds with URT diagnosis (median = 7.81 years). Dogs with high risk for URT disorders had more co-morbidities than average.


Methods
This was a retrospective single cohort study based on data from Agria Djurförsäkring in Sweden. The insurance process has previously been described in detail 21 . There were two types of insurance: veterinary care and life, and dogs could be insured in either one or both. For dogs with veterinary care insurance, veterinary care costs were reimbursed and the insurance claim registered in the database if the costs exceeded the deductible amount. The veterinary care insurance had no upper age limit, while life insurance was terminated at the age of eight, 10, or 12 years, depending on breed (see supplementary Table 1), and owners were reimbursed when the dog died or was euthanised. Claims for conditions not covered by the insurance (for example vaccination, dental care, and certain congenital disorders) were not registered. For URT disorders, the only exemptions from veterinary care insurance during this period were for the surgical treatment of conditions affecting the nostrils, soft palate, trachea and pharynx in the Boston terrier, French and English bulldog and pug. However, owners of the aforementioned breeds were reimbursed for diagnosis and medical treatment of conditions affecting the upper airways throughout the observation period. After April 1 st , 2014, the Boston terrier, French and English bulldog and the pug were excluded from all veterinary care for conditions affecting the nostrils, soft palate, trachea and pharynx.

Study population.
Inclusion criteria were all dogs insured for veterinary care by Agria Djurförsäkring, Sweden at any time between 1 st January 2011 and 31 st March 2014. Sex was recorded as either female or male, as information on neutering status was unavailable. Exclusion criteria were dogs solely enrolled for life insurance and dogs for which information about breed, sex, birth year, age or date of enrolment was uncertain or missing.
Data collection. For each dog the following variables were retrieved from the database: date of birth, date of death (if available), breed, sex, date when the dog entered and left the insurance programme, type of insurance (veterinary care or veterinary care and concurrent life insurance), date of claim and diagnostic code(s) (if any).
Diagnostic classification. The diagnostic code(s) were assigned by the attending veterinarian based on the hierarchical diagnostic registry developed by the Swedish Association of Veterinary Clinics and Hospitals 22 . Diagnoses in this registry are classified according to organ system, for example cardiovascular or respiratory, and disease process, for example neoplastic or inflammatory. The date of diagnosis and death in the Agria database corresponded to the date when the claim was registered. If receipts from several veterinary appointments within a 125-day insurance period were submitted at the same time, these were usually coded in separate claims but registered at the same date. For the purposes of this study the upper respiratory system included the trachea, but www.nature.com/scientificreports/ not the bronchi 23,24 . The URT diagnostic codes used included both presenting complaints such as "cough from the upper airway", "increased noise from the upper airway" and more specific diagnoses, such as "elongated soft palate", "tracheal collapse", and are listed in supplementary  26 . Bonferroni (BF) correction for multiple comparisons was used to adjust the significance level and p-values of < 0.05 after corrections were considered significant. A forest plot from the R-package "forestplot" (version 1.9) was used to describe breed risks 27 . Breeds with significantly higher RR for URT diagnosis were termed "high-risk breeds". Median age at first URT diagnosis was calculated for high-risk breeds, and Wilcoxon rank sum test was used to compare the age at first URT-diagnosis between breeds, and between brachycephalic and non-brachycephalic breeds. In dogs with URT diagnoses and concurrent life insurance, age at life claim (age at death) was calculated for dogs that died/ were euthanised during the observation period. The age at death for each high-risk breed was compared to the age at death for all other breeds with URT diagnoses. Only high-risk breeds with more than six cases of death/ euthanasia were included in this analysis.
Co-morbidity was evaluated for dogs of high-risk breeds. For dogs with URT claims, previous and subsequent diagnoses from the start of the observation period until 31 December 2016 or withdrawal from the insurance were retrieved. Each high-risk dog was compared with five randomly chosen age-matched control dogs (= dogs with no URT diagnosis). Previous/subsequent diagnoses were compared between cases and controls using conditional logistic regression, with URT-diagnosis as the main exposure variable and previous/subsequent diagnoses as outcome. For cases, co-morbidities diagnosed at the same date as the first URT diagnosis were excluded.  Table 1.

Results
A total of 6590 claims for URT disorders were registered in 4781 dogs. The overall IR for URT disease was 50.56 (CI; 49.14-52.01) cases per 10,000 DYAR. Of 327 breeds in the database, 205 breeds had at least one dog with an URT veterinary care diagnosis. Thirteen breeds had a significantly increased risk and two breeds a significantly decreased risk for URT disorders after BF correction (Fig. 1). Among 13 high-risk breeds, eight were brachycephalic and five were non-brachycephalic ( Table 2). The English bulldog, Japanese chin, Pomeranian, Norwich terrier, and pug had the highest IR of URT disorders. Median age at first URT diagnosis was 6.00 years (IQR 2.59-9.78), and varied with breed. The English and French bulldog, pug, Chihuahua and Boxer had a significantly lower age than average at first URT diagnosis after BF correction (Fig. 1). Brachycephalic high-risk breeds were younger (p < 0.001) at first URT diagnosis (4.29 years, IQR; 1.73-6.66) compared to non-brachycephalic high-risk breeds (4.97 years, IQR; 1.83-9.19).
Male dogs had an increased risk of having an URT diagnosis compared to female dogs (RR 1.19, CI; 1.12-1.26, p < 0.001). The pug was the only high-risk breed for which male dogs had an increased risk compared to female dogs, after BF correction (RR 1.91, CI; 1.28-2.89, p < 0,001). Of 935 dogs of a high-risk breed with an URT diagnosis in the veterinary care database, 682 (72.9%) had a concurrent life insurance. Of these, 140 dogs (20.5%) had a life insurance settlement, irrespective of cause, during the observation period. The median age at life claim event (death or euthanasia) in all dogs with URT-diagnoses was 7.81 (IQR; 5.66-9.31) years and varied with  (Table 3). French bulldogs with URT diagnosis were significantly younger (3.62 years, IQR; 1.89-6.72) at death/euthanasia compared to all other dogs with URT diagnosis, after BF correction. The odds of having registered co-morbidities before/after the first URT claim, compared to age-matched controls, varied with breed and is detailed in Table 4. With the exception of the Boston-, Norwich-, Yorkshire terrier, and Japanese chin, all other high-risk breeds had increased odds for co-morbidity during the observation period. The boxer, CKCS, Chihuahua, French bulldog, pug and standard poodle had high risk for co-morbidity both prior and after the first URT claim.

Discussion
To our knowledge, this is the first published large-scale study to report the epidemiology of URT disorders with focus on breed-specific risks. We found that URT disorders were common, and identified 13 high-risk breeds, eight of which were brachycephalic. High-risk dog breeds had their first URT diagnosis at a median age of approximately 6 years, and had an increased disease burden compared to average. Brachycephalic high-risk breeds acquired their first URT diagnosis at a younger age than non-brachycephalic high-risk breeds.
The overall IR of URT diagnosis was 50.56 cases per 10,000 DYAR in the cohort studied. This is comparable to the incidence of respiratory disorders reported in a recent study on presenting complaints and diagnosis distribution in Australian dogs based on insurance data 3 . Respiratory disorders were the fifth most common diagnostic category after gastrointestinal, dermatological, urogenital and other (unspecified) disorders in an earlier study on the distribution of diagnosis in Swedish dogs insured in Agria Djurförsäkring 1 .
Thirteen breeds were identified with increased risk of URT disorders. Two of these, the Japanese chin and standard poodle, which are relatively uncommon breeds, have to our knowledge no previously reported URT Figure 1. Breeds with significantly higher and lower RR for URT disorders after BF correction (significance level after BF correction 0.05/327). Breeds above the grey line had a significantly increased RR, and mixed breed and German shepherd dog (below the grey line) had a significantly decreased risk. *age at first URT diagnosis significantly different from all 205 breeds with URT diagnosis. **age at first URT diagnosis significantly different from 205 breeds with URT diagnosis after BF correction (significance level after BF correction 0.05/205). DYAR : dog years at risk; CI: confidence interval; RR: relative risk; URT: upper respiratory tract; BF: Bonferroni. www.nature.com/scientificreports/ disorder predisposition. It is possible that our results reflect a regional disease variation, or, that URT disorders not historically common in these breeds are becoming increasingly prevalent, or, that being uncommon breeds, predispositions may be difficult to identify. The Japanese chin, a brachycephalic breed, has recently been included in case series on BOAS and epiglottic retroversion (displacement of the epiglottis into the larynx lumen resulting in inspiratory airflow limitation and/or distress) 28,29 and being a toy breed, may have a predisposition to tracheal collapse 30,31 . Toy breeds like the Japanese chin, Chihuahua and Pomeranian have undergone exaggerated miniaturization. As a consequence, the vomerine alae can be too large in relation to the lumen, leaving an air passage of 1 mm or less at the level of the meatus nasopharyngeus (the passage from the nasal cavity to the pharynx) 32 . This can result in stertorous breathing, excessive reverse sneezing and nasal discharge, which are common URT presenting complaints in these breeds 32 .
All remaining 11 high-risk breeds have a previously reported susceptibility to URT disorders. The Boston terrier, boxer, CKCS, English and French bulldog and pug are brachycephalic breeds and affected to a variable degree by BOAS 5,33-35 . The Norwich terrier, often classified as a mesaticephalic breed, suffers from Norwich Terrier Upper Airway Syndrome (NTUAS), an obstructive disorder that has features similar to, but also distinct from BOAS 11,36 . The Irish wolfhound is susceptible to rhinitis, and respiratory infections 5 . The Chihuahua, CKCS, Pomeranian and Yorkshire terrier are breeds frequently affected with the URT disorder tracheal collapse 5,[37][38][39][40] .
Although the brachycephalic breeds most often cited in association with URT disorders are the English and French bulldog, the pug and the Boston terrier, our study found that the Japanese chin, Pomeranian, CKCS and boxer also have an increased risk for URT disorders. Among 13 breeds with high RR for URT disorders in this study, eight (Boston terrier, boxer, CKCS, English bulldog, French bulldog, Japanese chin, Pomeranian, pug) are recognised as brachycephalic by most researchers 28,41,42 . However, depending on the definition of brachycephaly, some authors suggest that the Chihuahua may be included in this category or that the Pomeranian be Table 3. Median age at death/euthanasia for high-risk breed dogs with URT diagnoses in a cohort of insured Swedish dogs. Only breeds with more than six dogs are included. *The French bulldog was the only breed with significantly lower median age at death/euthanasia after BF correction, compared to all other dogs with URTdiagnoses (significance level after correction 0.05/13).   28 . This shows a definite overrepresentation of brachycephalic breeds among breeds most at risk for URT disorders. The brachycephalic conformation has been linked to an increased risk for URT disorders, and specifically BOAS, in the French and English bulldog, the CKCS, Boston terrier and the pug [4][5][6][7][42][43][44] . This study has the advantage of presenting further and strong evidence to this fact, by investigating a large sample population, which is representative of the Swedish dog population 15 . Some brachycephalic breeds have had a recent surge in popularity, which has in turn led to an increased frequency of veterinary care events for health issues commonly affecting these breeds. For example, a recent study found that corrective surgery for BOAS markedly increased in Swedish veterinary clinical practice between the years 2014 and 2016 45 . However, it remains unclear to which extent the brachycephalic conformation contributes to the increased risk for URT disorders found in this study for the Japanese chin, Pomeranian and boxer. Further studies are necessary to investigate if there is a conformational inference to the URT disorders found in these breeds. Male dogs had a slightly increased risk for URT disorders, which is in accordance with an earlier Swedish study reporting a male predisposition to respiratory disease 1 . Stratified by breed within high-risk breeds, this predisposition was significant only for the pug; male pugs had twice the odds of URT disorders compared to females. This result contrasts findings in a UK-based study in which female pugs were five times more at risk of BOAS compared to males 44 . Possible reasons for this might be an actual difference between pug populations in the two countries or that the recruited population used in the single-centred UK study was not entirely representative of the national pug population (selection bias).
Median age at first URT diagnosis varied with breed, most probably reflecting the different age that various disorders manifest. Laryngeal paralysis for example typically affects older dogs, NTUAS middle-aged to older dogs, whereas BOAS presents at a younger age 11,28,39 . Median age at first diagnosis was significantly lower for the English and French bulldog, pug, boxer and Chihuahua compared to all other breeds with URT diagnosis. A possible explanation for this is that these breeds are affected with congenital and/or developmental disorders, which as a rule present early in life. A sudden surge in breed popularity, as has been noted for the Chihuahua and the French bulldog 14,[46][47][48] , might also lead to a generally younger population of these breeds presented in the database with URT diagnosis, with relatively fewer older dogs registered with an URT diagnosis. In contrast, breeds with constant registration numbers would have a population with a more balanced age distribution. If the bulk of dogs present in the dataset are relatively young, this will bias the age at first URT diagnosis downwards in these breeds. Among 13 high-risk breeds, eight brachycephalic breeds were diagnosed with an URT diagnosis almost one year earlier than five non-brachycephalic breeds. Several factors can contribute to this, for example a predilection of brachycephalic breeds to congenital and/or developmental disorders, or a relatively young population in some of the brachycephalic breeds in the database, as earlier mentioned. However, it is still noteworthy that brachycephalic breeds acquire a URT-related disease burden earlier in life compared to non-brachycephalic breeds, as this disorder may have a negative influence on their life quality for a larger proportion of their lives compared to the non-brachycephalic breeds.
The average lifespan of dogs with URT disorders was 7.81 years in this study. Recent studies based on collection of primary care data published a 12-and 10-year average life expectancy for the general dog population in the UK and Denmark respectively [49][50][51] . However, life expectancy calculations based on life insurance data, which pertain an inherent upper age limit will probably bias the average lifespan downwards compared with primary care data or questionnaire studies observing dogs throughout their lifetime. Longevity varies with dog breed, and is generally inversely related to breed size, with large-sized and giant breeds usually having a shorter lifespan than medium-and small-sized breed dogs [49][50][51] . With the exception of the Irish wolfhound, all other high-risk breeds in this study were of medium to small size, and therefore an average lifespan of 10 to 12 years might be expected [49][50][51][52] . Notably, French bulldogs with URT disorders had a dramatically shorter lifespan (3.6 years) than the normal life expectancy in this small-sized dog. The average lifespan recently reported for the French and English bulldog and the pug (8.6 years) was approximately 3 years shorter compared to like-sized mesaticephalic and dolichocephalic breeds 4 . The authors suggested that BOAS and other conformational disorders common in these breeds lead to an earlier death 4 . French bulldogs have higher odds for several serious health issues compared to the average dog population 53 . Many of these predispositions have been attributed to their extreme brachycephalic conformation, suggesting that breeding for a less extreme exterior could improve the general health in this breed 53 . The short average lifespan of French bulldogs with URT disorders in our study is probably the result of an exceptionally high disease burden in this breed. However, a relatively young population of French bulldogs in the database (due to a sudden surge in popularity of this breed) could also contribute to a lower age at death. Moreover, attitudes to disease, death, and euthanasia among owners and veterinarians will also affect a dog's lifespan. These attitudes can vary significantly between countries due to societal differences. The impact of such attitudes on the decision to pursue continued health care or opt for euthanasia can be hard to measure.
Most of the high-risk breeds for URT disorders had increased odds for co-morbidities; thereby appearing to be less healthy than the general dog population. This could reflect an actual higher disease burden in these breeds, as has for example been shown for the French bulldog 53 . The English bulldog and the CKCS are also prone to a high disease load 5 . In Norway recently, a court ruled that breeding English bulldogs and CKCSs contravened the country´s animal welfare act, and imposed a ban on these breeds. However, the court allowed for modified breeding practices, such as crossbreeding, aiming to alleviate these breeds' significant health problems 54 . Although our study provides some information on the disease burden of high-risk breeds for URT disorders, it was not designed to present comprehensive breed-specific disease predispositions. Studies investigating specific breeds' disease susceptibilities are relatively scarce in the veterinary literature. Such studies could provide information on the overall health issues of individual breeds, which would be valuable for veterinarians, breeders, prospective dog owners, and policy makers. Economic factors, veterinary care availability and personality traits might have an impact on owners' decision to seek veterinary care 55  www.nature.com/scientificreports/ and owners with a strong bond to their dogs may be more prone to seek veterinary care, contributing thus to a seemingly bigger disease load in their dogs. Epidemiologic data can be collected by different methods, each subject to limitations. Questionnaire-based surveys are easy to distribute and may be representative of the entire population, but are subject to potentially low response rates, diagnostic inaccuracy and responder and recall bias. Data from referral hospital records have high diagnostic and demographic accuracy, but introduce a potential selection bias, because more complex clinical cases will be represented in this material. Data from primary care records may be more representative of the population at risk than referral hospital data, but similar to referral hospital data, contain no information on the healthy background population. Large-scale epidemiologic data can be retrieved from insurance databases, which, unlike hospital data, contain information on both cases and the insured healthy background population, from the start until the end of a dog´s insurance period. When a sufficient proportion of a country´s dog population is insured, findings can be generalised to the national dog population. In Sweden, 77% of all dogs were covered by veterinary insurance, with approximately 50% of those enrolled in Agria Djurförsäkring during the year 2012 13,14 . The Agria Djurförsäkring database has been validated against veterinary practice records and found to have excellent agreement (> 94%) for demographic data such as breed and sex, and fair agreement (85%) for diagnostic accuracy and date of birth, thus rending the quality of the database adequate to support ongoing research 56 . Another advantage is that the dataset is large, allowing for significant statistical power, with the exception of rare breeds with a limited number of individuals.
Limitations associated with utilising insurance databases in research have been described in detail 55 but some that apply to this study must be mentioned. Selection bias introduced by claim excess amounts and condition exclusions from pet insurance cover lead to an unknown number of unregistered cases. A veterinary care event must rend a cost exceeding the deductible amount for the event to be registered in the database, thus a number of cases will go undetected. However, this most probably affects the general IR of URT disorders, and not breedspecific results. During the study observation period, the only URT-related exclusion from insurance coverage was for the surgical treatment of conditions affecting the nostrils, soft palate, trachea and pharynx in the Boston terrier, French and English bulldog and pug. Further, several studies report that owners and veterinarians will often accept clinical signs of BOAS until they are severe, which consequently adds to the number of undetected and undiagnosed cases 9,43,57 . Consequently, the true incidence of URT disorders in these breeds is most probably much higher than reported in this study.
Another limitation is that results from epidemiological studies based on insured populations may not be valid in uninsured animals 55 . In Sweden, although the vast majority (77% percent) of dogs were insured in 2012 14 , there may still be differences between the insured and uninsured dog population; an earlier study found that insurance coverage varied somewhat with breed 58 .
The inclusion of tracheal disorders in this study may be considered controversial, as the trachea is usually classified as part of the lower respiratory tract in the literature. The distinction between upper and lower airway is not clear, and some researchers might even include the larynx in the lower airway. However, many clinicians and part of the veterinary literature consider the cervical trachea and the larynx as part of the upper airway 23,24,59 . As the diagnostic codes in this study were assigned by clinicians, we have chosen to include the trachea in our list of URT diagnoses.
Finally, BF correction was applied to adjust for multiple comparisons, but it should be noted that the likelihood of type II errors increases when BF correction is applied. However, as the sample size in the current study is large, a type II error should be regarded as less probable.

Conclusions
In conclusion, URT disorders affected almost 5000 dogs in this study population, with an incidence of 50.56 (95 CI; 49.14-52.01) cases per 10,000 DYAR. Our study confirmed previously known breed predispositions for URT disorders, and identified two unreported breeds at risk. Besides BOAS in brachycephalic breeds, a breed predisposition for other URT diagnoses in non brachycephalic breeds were verified. We found a definite overrepresentation of brachycephalic breeds among breeds with high RR for URT disorders. The epidemiological information associated with URT disorders in this study can be of value for veterinarians in clinical-and research settings. In addition, our results provide educational information on breed-related health risks for breeders, dog owners and policy makers.

Data availability
The data analysed in the current study are not publicly available due to a non-disclosure agreement with Agria Djurförsäkring.